Dysregulated ERK/MAPK signaling is increasingly implicated as causative in neurodevelopmental syndromes. Cognitive disability can be associated with mutations in canonical components of the RAF/MEK/ERK cascade as well as in upstream modifiers or downstream mediators, and can be associated with either loss or gain of function through the pathway. Collectively, these syndromes are referred to as or Rasopathies or Ras/MAPK syndromes. A key impediment to understanding cognitive deficits in Ras/MAPK syndromes is that we know almost nothing about the cell type specific consequences of disrupted ERK/MAPK signaling in the developing brain. A powerful recently emerging concept is that excitatory / inhibitory imbalance underlies the behavioral deficits in many neurodevelopmental disorders. However, the extent to which this concept applies to Ras/MAPK syndromes is unclear. Therefore in Aims 1 and 2 we propose to define the consequences of reduced and enhanced ERK/MAPK signaling for morphological and physiological development of cortical excitatory (Aim 1) versus cortical inhibitory (Aim 2) neurons. A key issue for therapeutics is the potential for reversibility of neurological deficits if ERK/MAPK signaling can be normalized during a critical neurodevelopmental period postnatally. Because ERK can be modified to allow a chemical genetic approach, the ERK/MAPK pathway provides a perfect paradigm to explore reversibility of neurodevelopmental deficits in mouse models. To this end, in Aim 3, we will develop a chemical genetic, cell type specific paradigm for normalizing dysregulated ERK/MAPK signaling in specific classes of cortical neurons. PUBLIC HEALTH RELEVANCE: Recently mutations in genes that code for components of an important intracellular signaling pathway (ERK/MAPK) have been shown to cause neurodevelopmental delay as well as cardiac and craniofacial abnormalities. In order to understand cognitive disability in these syndromes we propose to perturb this ERK/MAPK pathway in specific cell types in the developing brains of experimental animals. In order to develop new strategies for therapeutics we plan to generate an animal model that allows reversal of ERK/MAPK signaling abnormalities in postnatal animals.